scholarly journals Emergence of ion channel modal gating from independent subunit kinetics

2016 ◽  
Vol 113 (36) ◽  
pp. E5288-E5297 ◽  
Author(s):  
Brendan A. Bicknell ◽  
Geoffrey J. Goodhill
Keyword(s):  
Ion Channels ◽  
Conformational Changes ◽  
Ionic Currents ◽  
Analytical Framework ◽  
Stochastic Simulations ◽  
Coarse Grained ◽  
Wide Range ◽  
Intracellular Ca ◽  
Modal Gating ◽  
Kinetics Of

Many ion channels exhibit a slow stochastic switching between distinct modes of gating activity. This feature of channel behavior has pronounced implications for the dynamics of ionic currents and the signaling pathways that they regulate. A canonical example is the inositol 1,4,5-trisphosphate receptor (IP3R) channel, whose regulation of intracellular Ca2+ concentration is essential for numerous cellular processes. However, the underlying biophysical mechanisms that give rise to modal gating in this and most other channels remain unknown. Although ion channels are composed of protein subunits, previous mathematical models of modal gating are coarse grained at the level of whole-channel states, limiting further dialogue between theory and experiment. Here we propose an origin for modal gating, by modeling the kinetics of ligand binding and conformational change in the IP3R at the subunit level. We find good agreement with experimental data over a wide range of ligand concentrations, accounting for equilibrium channel properties, transient responses to changing ligand conditions, and modal gating statistics. We show how this can be understood within a simple analytical framework and confirm our results with stochastic simulations. The model assumes that channel subunits are independent, demonstrating that cooperative binding or concerted conformational changes are not required for modal gating. Moreover, the model embodies a generally applicable principle: If a timescale separation exists in the kinetics of individual subunits, then modal gating can arise as an emergent property of channel behavior.

The Croonian Lecture, 1983 - Voltage-gated ion channels in the nerve membrane

1983 ◽  
Vol 220 (1218) ◽  
pp. 1-30 ◽  
Keyword(s):  
Ion Channels ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Essential Feature ◽  
Ionic Currents ◽  
Fluctuation Analysis ◽  
Gating Current ◽  
Nervous Impulse ◽  
Voltage Gated Ion Channels ◽  
Kinetics Of

In the Croonian Lecture for 1957, Sir Alan Hodgkin described the role of the channels selective for sodium and potassium ions in the conduction of the nervous impulse. An essential feature of these channels is the manner in which the complex kinetics of their opening and closing is controlled by the electric field across the membrane, and the purpose of the present lecture is to consider the advances that have been made in the past 25 years towards an understanding of the underlying molecular mechanisms. One such advance has been the successful recording, independently of the ionic currents, of the small asymmetry current known as the gating current, that accompanies the conformational changes that take place in the sodium channels. A quantitative analysis of the characteristics of the gating current suggests that activation is brought about by two more or less independent processes operating in parallel, to one of which the slower mechanism of inactivation is coupled sequentially. However, it is clear that a complete picture of the gating system will only be arrived at by combining evidence of this kind with that provided by other new lines of approach such as studies of single ion channels in various tissues by means of fluctuation analysis and the patch-clamping technique, and a reinvestigation of the kinetics of activation of the potassium channels.

scholarly journals Mechanistic insights from resolving ligand-dependent kinetics of conformational changes at ATP-gated P2X1R ion channels

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Alistair G. Fryatt ◽  
Sudad Dayl ◽  
Paul M. Cullis ◽  
Ralf Schmid ◽  
Richard J. Evans
Keyword(s):  
Ion Channels ◽  
Conformational Changes ◽  
Kinetics Of

Calcium Channels in the Development, Maturation, and Function of Spermatozoa

2011 ◽  
Vol 91 (4) ◽  
pp. 1305-1355 ◽  
Author(s):  
Alberto Darszon ◽  
Takuya Nishigaki ◽  
Carmen Beltran ◽  
Claudia L. Treviño
Keyword(s):  
Ion Channels ◽  
Male Infertility ◽  
Captive Breeding ◽  
Male Gamete ◽  
Ionic Currents ◽  
Assisted Conception ◽  
Unique Event ◽  
Intracellular Ca ◽  
And Function ◽  
Multiple Signaling

A proper dialogue between spermatozoa and the egg is essential for conception of a new individual in sexually reproducing animals. Ca2+ is crucial in orchestrating this unique event leading to a new life. No wonder that nature has devised different Ca2+-permeable channels and located them at distinct sites in spermatozoa so that they can help fertilize the egg. New tools to study sperm ionic currents, and image intracellular Ca2+ with better spatial and temporal resolution even in swimming spermatozoa, are revealing how sperm ion channels participate in fertilization. This review critically examines the involvement of Ca2+ channels in multiple signaling processes needed for spermatozoa to mature, travel towards the egg, and fertilize it. Remarkably, these tiny specialized cells can express exclusive channels like CatSper for Ca2+ and SLO3 for K+, which are attractive targets for contraception and for the discovery of novel signaling complexes. Learning more about fertilization is a matter of capital importance; societies face growing pressure to counteract rising male infertility rates, provide safe male gamete-based contraceptives, and preserve biodiversity through improved captive breeding and assisted conception initiatives.

The kinetics of voltage-gated ion channels

1994 ◽  
Vol 27 (4) ◽  
pp. 339-434 ◽  
Author(s):  
R. D. Keynes
Keyword(s):  
Ion Channels ◽  
Ionic Currents ◽  
Giant Axon ◽  
General Information ◽  
Squid Giant Axon ◽  
Voltage Gated ◽  
Voltage Gated Ion Channels ◽  
Kinetics Of ◽  
Electrical Data ◽  
Gated Ion Channels

When Hodgkin & Huxley (1952) first embarked on the analysis of their voltageclamp data on the ionic currents in the squid giant axon, they hoped to be able to deduce a mechanism from it, but it soon became clear that the electrical data would by themselves yield only very general information about the class of system likely to be involved.

scholarly journals Electrostatics and Solvation: Essential Determinants of Chromatin Compaction

2019 ◽  
Author(s):  
A. Bendandi ◽  
S. Dante ◽  
S. Rehana Zia ◽  
A. Diaspro ◽  
W. Rocchia
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Electrostatic Interactions ◽  
Ionic Concentration ◽  
Coarse Grained ◽  
Chromatin Compaction ◽  
Spatial And Temporal Scales ◽  
Chromatin Fibre ◽  
Nucleosome Core ◽  
Wide Range

ABSTRACTChromatin compaction is a process of fundamental importance in Biology, as it greatly influences cellular function and gene expression. The dynamics of compaction is determined by the interactions between DNA and histones, which are mainly mechanical and electrostatic. The high charge of DNA makes electrostatics extremely important for chromatin topology and dynamics. Besides their mechanical and steric role in the chromatin fibre, linker DNA length and linker histone presence and binding position also bear great electrostatic consequences. Electrostatics in chromatin is also indirectly linked to the DNA sequence: the presence of high-curvature AT-rich segments in DNA can cause conformational variations with electrostatic repercussions, attesting to the fact that the role of DNA is both structural and electrostatic. Electrostatics in this system has been analysed by extensively examining at the computational level the repercussions of varying ionic concentration, using all-atom, coarse-grained, and continuum models. There have been some tentative attempts to describe the force fields governing chromatin conformational changes and the energy landscapes of these transitions, but the intricacy of the system has hampered reaching a consensus. Chromatin compaction is a very complex issue, depending on many factors and spanning orders of magnitude in space and time in its dynamics. Therefore, comparison and complementation of theoretical models with experimental results is fundamental. Here, we present existing approaches to analyse electrostatics in chromatin and the different points of view from which this issue is treated. We pay particular attention to solvation, often overlooked in chromatin studies. We also present some numerical results on the solvation of nucleosome core particles. We discuss experimental techniques that have been combined with computational approaches and present some related experimental data such as the Z-potential of nucleosomes at varying ionic concentrations. Finally, we discuss how these observations support the importance of electrostatics and solvation in chromatin models.SIGNIFICANCEThis work explores the determinants of chromatin compaction, focusing on the importance of electrostatic interactions and solvation. Chromatin compaction is an intrinsically multiscale issue, since processes concerning chromatin occur on a wide range of spatial and temporal scales. Since DNA is a highly charged macromolecule, electrostatic interactions are extremely significant for chromatin compaction, an effect examined in this work from many angles, such as the importance of ionic concentration and different ionic types, DNA-protein interactions, and solvation. Solvation is often overlooked in chromatin studies, especially in coarse-grained models, where the nucleosome core, the building block of the chromatin fibre, is represented as a rigid body, even though it has been observed that solvation influences chromatin even at the base-pair level.

scholarly journals Cooperation within von Willebrand factors enhances adsorption mechanism

2015 ◽  
Vol 12 (109) ◽  
pp. 20150334 ◽  
Author(s):  
Maziar Heidari ◽  
Mehrdad Mehrbod ◽  
Mohammad Reza Ejtehadi ◽  
Mohammad R. K. Mofrad
Keyword(s):  
Conformational Changes ◽  
Van Der Waals Interactions ◽  
Coarse Grained ◽  
Collagen Fibres ◽  
Receptor Field ◽  
Adsorption Dynamics ◽  
Shear Rates ◽  
Collagen Receptors ◽  
Wide Range ◽  
Von Willebrand

von Willebrand factor (VWF) is a naturally collapsed protein that participates in primary haemostasis and coagulation events. The clotting process is triggered by the adsorption and conformational changes of the plasma VWFs localized to the collagen fibres found near the site of injury. We develop coarse-grained models to simulate the adsorption dynamics of VWF flowing near the adhesive collagen fibres at different shear rates and investigate the effect of factors such as interaction and cooperativity of VWFs on the success of adsorption events. The adsorption probability of a flowing VWF confined to the receptor field is enhanced when it encounters an adhered VWF in proximity to the collagen receptors. This enhancement is observed within a wide range of shear rates and is mostly controlled by the attractive van der Waals interactions rather than the hydrodynamic interactions among VWF monomers. The cooperativity between the VWFs acts as an effective mechanism for enhancing VWF adsorption to the collagen fibres. Additionally, this implies that the adsorption of such molecules is nonlinearly dependent on the density of flowing VWFs. These findings are important for studies of primary haemostasis as well as general adsorption dynamics processes in polymer physics.

Kinetics of [Ca]i decline in cardiac myocytes depend on peak [Ca]i

1995 ◽  
Vol 268 (1) ◽  
pp. C271-C277 ◽  
Author(s):  
D. M. Bers ◽  
J. R. Berlin
Keyword(s):  
Ventricular Myocytes ◽  
Transport Rate ◽  
Transport Systems ◽  
Ca Transport ◽  
Rat Hearts ◽  
Wide Range ◽  
Intracellular Ca ◽  
Rate Of Decline ◽  
Kinetics Of ◽  
Peak Value

The rate of decline of free intracellular Ca concentration ([Ca]i) is a potentially useful index of the function of Ca transport systems. However, interpretations of these results may depend on multiple Ca transport systems and interaction with intracellular Ca binding sites. We measured [Ca]i in voltage-clamped ventricular myocytes isolated from rat hearts using indo 1 fluorescence. Conditions were chosen where [Ca]i decline was expected to depend almost exclusively on the sarcoplasmic reticulum Ca pump. The half time of [Ca]i decline (t1/2) decreased as the amplitude of the intracellular Ca (Cai) transient increased. This is not the result that would be expected from a transport system where the transport rate is a linear function of free [Ca]i. In this case the time constant of [Ca]i decline (tau) should be independent of the peak value of [Ca]i. This is also true if linear buffering of Cai is included. We develop a simple but more realistic theoretical framework where Ca transport rate and Ca binding both depend on free [Ca]i with Michaelis-Menten type functions. We demonstrate that the observed decline in apparent tau with increasing peak [Ca]i is entirely expected on theoretical grounds and over a wide range of characteristics for Ca transport and binding. We conclude that one cannot draw inferences about the intrinsic Ca transport function based on tau values unless the Cai transient has a comparable size.

scholarly journals Egg activation is the result of calcium signal summation in the mouse

Reproduction ◽  
2006 ◽  
Vol 131 (1) ◽  
pp. 27-34 ◽  
Author(s):  
Szabolcs Tóth ◽  
Daniel Huneau ◽  
Bernadette Banrezes ◽  
Jean-Pierre Ozil
Keyword(s):  
Developmental Stages ◽  
Biological Effects ◽  
Egg Activation ◽  
Calcium Signal ◽  
Wide Range ◽  
Transduction Mechanisms ◽  
Intracellular Ca ◽  
Pronuclear Formation ◽  
Kinetics Of ◽  
Mouse Eggs

Egg activation in mammals is caused by cytosolic Ca2+ oscillations that are essential for development. However, despite increasing knowledge about signal transduction mechanisms, the functional linkage between frequency number, amplitude and duration of the Ca2+ signal and the kinetics of pronucleus formation has not yet been defined. While a wide range of Ca2+ signal parameters are efficient in causing egg activation, the basic rules governing how the egg integrates these signalling events are not yet clear. Thus, in the perspective of better understanding how the egg processes Ca2+ signalling events, the objective of this study was to determine experimentally whether the efficiency of egg activation and the subsequent early developmental stages rely on Ca2+ signalling summation. Non-fertilized, but freshly ovulated mouse eggs, were subjected to a series of repetitive Ca2+ influxes of various patterns modulated by a non-invasive membrane electropermeabilization method. Using a combination of two suboptimal treatments we have shown that mouse eggs can sum up the effects caused by various patterns of intracellular Ca2+ concentrations transient during the period of egg activation. In addition, overloading the intracellular milieu by repetitive Ca2+ influxes did not seem to inhibit the process of activation. The kinetics of pronuclear formation among a population of eggs treated in the same conditions became accelerated when the total dose of Ca2+ signal ‘experienced’ by the eggs was increased. The results suggested that summation of the biological effects of all Ca2+ signals constitutes an important mode of Ca2+ signal integration.

Patterns in diversity and composition of the microbenthos of subarctic intertidal beaches with different morphodynamics

2020 ◽  
Vol 648 ◽  
pp. 19-38
Author(s):  
AI Azovsky ◽  
YA Mazei ◽  
MA Saburova ◽  
PV Sapozhnikov
Keyword(s):  
Species Abundance ◽  
Abundance Ratio ◽  
Wave Action ◽  
Coarse Grained ◽  
Sediment Properties ◽  
Β Diversity ◽  
Α Diversity ◽  
Wide Range ◽  
Similar Mode ◽  
Abundance And Diversity

Diversity and composition of benthic diatom algae and ciliates were studied at several beaches along the White and Barents seas: from highly exposed, reflective beaches with coarse-grained sands to sheltered, dissipative silty-sandy flats. For diatoms, the epipelic to epipsammic species abundance ratio was significantly correlated with the beach index and mean particle size, while neither α-diversity measures nor mean cell length were related to beach properties. In contrast, most of the characteristics of ciliate assemblages (diversity, total abundance and biomass, mean individual weight and percentage of karyorelictids) demonstrated a strong correlation to beach properties, remaining low at exposed beaches but increasing sharply in more sheltered conditions. β-diversity did not correlate with beach properties for either diatoms or ciliates. We suggest that wave action and sediment properties are the main drivers controlling the diversity and composition of the intertidal microbenthos. Diatoms and ciliates, however, demonstrated divergent response to these factors. Epipelic and epipsammic diatoms exhibited 2 different strategies to adapt to their environments and therefore were complementarily distributed along the environmental gradient and compensated for each other in diversity. Most ciliates demonstrated a similar mode of habitat selection but differed in their degree of tolerance. Euryporal (including mesoporal) species were relatively tolerant to wave action and therefore occurred under a wide range of beach conditions, though their abundance and diversity were highest in fine, relatively stable sediments on sheltered beaches, whereas the specific interstitial (i.e. genuine microporal) species were mostly restricted to only these habitats.

Scintigraphic studies in rats. Kinetics of insulin analogues covering wide range of receptor affinities

Diabetes ◽  
1991 ◽  
Vol 40 (5) ◽  
pp. 628-632 ◽  
Author(s):  
I. Jensen ◽  
V. Kruse ◽  
U. D. Larsen
Keyword(s):  
Insulin Analogues ◽  
Wide Range ◽  
Kinetics Of
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